The main purpose of this study is the investigation of the kinetics of serotonin uptake in the blood platelets of psychiatric patients and normal controls. Methodologic problems have hindered progress in this area. We have developed a reliable, sensitive assay which provides Km and Vmax for 3H-5-HT uptake. This method has been used to study 14 normal control, 16 depressed patients, 14 manic-depressive, manic-phase 5 acute and 5 chronic schizophrenics. All patients were unmedicated for at least a week at the time of blood sampling and were studied at least twice. Km of 5-HT uptake in the normal controls was found to be 0.50 plus or minus 0.13 microns which agrees with published results. Vamx was 4400 plus or minus 558 p moles/10 to the 9th power platelets/4 min. Both Km and Vmax of the depressed patients and chronic schizophrenics were significantly decreased. Km and Vmax of the 14 manic depressives and 5 acute schizophrenics were not significantly different from the controls. The 14 manic patients were further subdivided into those who reponded to lithium (n equals 8) and those who did not (N equals 6). During the placebo period, there was a tendency for Vmax in the responders to be significantly higher than that of the nonresponders without any difference in Km. However, after two-four weeks of lithium therapy, Km of the responders had significantly decreased from pretreatment levels as had Vmax. There was no change in Km and Vmax before and after lithium treatment in the non-responders. Both tricyclic antidepressants and MAO inhibitors were found to increase the Km for serotonin uptake in depressed patients. Studies are under way to relate Km and Vmax of 5-HT uptake to platelet 5-HT levels. Methods to fractionate the platelets by density gradient techniques are being developed.